The immune cell landscape in kidneys of patients with lupus nephritis

the Accelerating Medicines Partnership in SLE network

doi:10.1038/s41590-019-0398-x

The immune cell landscape in kidneys of patients with lupus nephritis

the Accelerating Medicines Partnership in SLE network

Research output: Contribution to journal › Article › peer-review

557 Scopus citations

Abstract

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.

Original language	English
Pages (from-to)	902-914
Number of pages	13
Journal	Nature Immunology
Volume	20
Issue number	7
DOIs	https://doi.org/10.1038/s41590-019-0398-x
State	Published - 1 Jul 2019
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

This work was supported by the Accelerating Medicines Partnership (AMP) in Rheumatoid Arthritis and Lupus Network. AMP is a public–private partnership (AbbVie Inc., Arthritis Foundation, Bristol-Myers Squibb Company, Foundation for the National Institutes of Health, Janssen Pharmaceuticals, Lupus Foundation of America, Lupus Research Alliance, Merck Sharp & Dohme Corp., National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer Inc., Rheumatology Research Foundation, Sanofi and Takeda Pharmaceuticals International, Inc.) created to develop new ways of identifying and validating promising biological targets for diagnostics and drug development. Funding was provided through grants from the National Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-AR067685, UH2-AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-AR067694 and UM2-AR067678). N.H. was supported by the David P. Ryan, MD Endowed Chair in Cancer Research. We thank participating Lupus Nephritis Trials Network clinical sites and participants.

Funders	Funder number
Foundation
Takeda Pharmaceuticals International, Inc.	UH2-AR067677, UH2-AR067688, UH2-AR067689, UH2-AR067679, UH2-AR067685, UM2-AR067678, UH2-AR067676, UH2-AR067691, UH2-AR067681, UH2-AR067694, UH2-AR067690
National Institutes of Health
National Human Genome Research Institute	U01HG009379
National Institute of Allergy and Infectious Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Arthritis Foundation
Lupus Foundation of America
Bristol-Myers Squibb
Pfizer
Sanofi
Rheumatology Research Foundation
AbbVie
Janssen Pharmaceuticals
Merck Sharp and Dohme
Lupus Research Alliance

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title = "The immune cell landscape in kidneys of patients with lupus nephritis",

abstract = "Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.",

author = "{the Accelerating Medicines Partnership in SLE network} and Arnon Arazi and Rao, {Deepak A.} and Berthier, {Celine C.} and Anne Davidson and Yanyan Liu and Hoover, {Paul J.} and Adam Chicoine and Eisenhaure, {Thomas M.} and Jonsson, {A. Helena} and Shuqiang Li and Lieb, {David J.} and Fan Zhang and Kamil Slowikowski and Browne, {Edward P.} and Akiko Noma and Danielle Sutherby and Scott Steelman and Smilek, {Dawn E.} and Patti Tosta and William Apruzzese and Elena Massarotti and Maria Dall{\textquoteright}Era and Meyeon Park and Kamen, {Diane L.} and Furie, {Richard A.} and Fernanda Payan-Schober and Pendergraft, {William F.} and McInnis, {Elizabeth A.} and Buyon, {Jill P.} and Petri, {Michelle A.} and Chaim Putterman and Kalunian, {Kenneth C.} and Woodle, {E. Steve} and Lederer, {James A.} and Hildeman, {David A.} and Chad Nusbaum and Soumya Raychaudhuri and Matthias Kretzler and Anolik, {Jennifer H.} and Brenner, {Michael B.} and David Wofsy and Nir Hacohen and Betty Diamond and Dia Waguespack and Connery, {Sean M.} and McMahon, {Maureen A.} and McCune, {William J.} and Kado, {Ruba B.} and Raymond Hsu and Cunningham, {Melissa A.}",

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year = "2019",

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doi = "10.1038/s41590-019-0398-x",

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AU - Davidson, Anne

AU - Liu, Yanyan

AU - Hoover, Paul J.

AU - Chicoine, Adam

AU - Eisenhaure, Thomas M.

AU - Jonsson, A. Helena

AU - Li, Shuqiang

AU - Lieb, David J.

AU - Zhang, Fan

AU - Slowikowski, Kamil

AU - Browne, Edward P.

AU - Noma, Akiko

AU - Sutherby, Danielle

AU - Steelman, Scott

AU - Smilek, Dawn E.

AU - Tosta, Patti

AU - Apruzzese, William

AU - Massarotti, Elena

AU - Dall’Era, Maria

AU - Park, Meyeon

AU - Kamen, Diane L.

AU - Furie, Richard A.

AU - Payan-Schober, Fernanda

AU - Pendergraft, William F.

AU - McInnis, Elizabeth A.

AU - Buyon, Jill P.

AU - Petri, Michelle A.

AU - Putterman, Chaim

AU - Kalunian, Kenneth C.

AU - Woodle, E. Steve

AU - Lederer, James A.

AU - Hildeman, David A.

AU - Nusbaum, Chad

AU - Raychaudhuri, Soumya

AU - Kretzler, Matthias

AU - Anolik, Jennifer H.

AU - Brenner, Michael B.

AU - Wofsy, David

AU - Hacohen, Nir

AU - Diamond, Betty

AU - Waguespack, Dia

AU - Connery, Sean M.

AU - McMahon, Maureen A.

AU - McCune, William J.

AU - Kado, Ruba B.

AU - Hsu, Raymond

AU - Cunningham, Melissa A.

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N2 - Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.

AB - Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.

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The immune cell landscape in kidneys of patients with lupus nephritis

Abstract

Bibliographical note

Funding

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